{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:56:21Z","timestamp":1787064981589,"version":"build-2736575974"},"reference-count":50,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,3,22]],"date-time":"2017-03-22T00:00:00Z","timestamp":1490140800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,3,22]],"date-time":"2017-03-22T00:00:00Z","timestamp":1490140800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Liver fibrosis is the most serious pathology caused by\n                    <jats:italic>Schistosoma japonicum<\/jats:italic>\n                    infection, which arises when schistosome eggs are deposited in the liver. Eosinophils, macrophages and hepatic stellate cells (HSCs) have been identified as major cellular contributors to the development of granulomas and fibrosis, but little is known about the effects of hepatocytes on granuloma formation. Here, we found that the levels of Wnt signalling-related molecules, transforming growth factor \u03b2 (TGF-\u03b2) and connective tissue growth factor (CTGF) in hepatocytes were markedly elevated after\n                    <jats:italic>S. japonicum<\/jats:italic>\n                    infection. Liver fibrosis was exacerbated when exogenous Wnt3a was introduced, but was alleviated when Wnt signalling was suppressed by DKK1, accompanied by the reduced expression of TGF-\u03b2 and CTGF in hepatocytes. These results indicate that the hepatocytic expression of TGF-\u03b2 and CTGF is mediated by Wnt signalling. Additionally, the hepatocytes isolated from infected mice promoted the activation of primary HSCs\n                    <jats:italic>in vitro<\/jats:italic>\n                    , however, this effect was not observed when hepatocytes from DKK1 treated\n                    <jats:italic>S. japonicum<\/jats:italic>\n                    -infected mice was employed in the co-culture system. Our findings identify a novel pro-fibrogenic role of hepatocytes in schistosomiasis-induced liver fibrosis that is dependent on Wnt signalling, which may serve as a potential target for ameliorating hepatic fibrosis caused by helminths.\n                  <\/jats:p>","DOI":"10.1038\/s41598-017-00377-4","type":"journal-article","created":{"date-parts":[[2017,3,13]],"date-time":"2017-03-13T06:58:57Z","timestamp":1489388337000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Enhanced Wnt Signalling in Hepatocytes is Associated with Schistosoma japonicum Infection and Contributes to Liver Fibrosis"],"prefix":"10.1038","volume":"7","author":[{"given":"Qi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Chou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengming","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengjun","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Lei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yonglong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenqi","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,3,22]]},"reference":[{"key":"377_CR1","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.pt.2013.12.009","volume":"30","author":"C Chuah","year":"2014","unstructured":"Chuah, C., Jones, M. K., Burke, M. L., McManus, D. P. & Gobert, G. N. Cellular and chemokine-mediated regulation in schistosome-induced hepatic pathology. Trends in parasitology \n                           30, 141\u2013150, doi:10.1016\/j.pt.2013.12.009 (2014).","journal-title":"Trends in parasitology"},{"key":"377_CR2","doi-asserted-by":"publisher","first-page":"2253","DOI":"10.1016\/S0140-6736(13)61949-2","volume":"383","author":"DG Colley","year":"2014","unstructured":"Colley, D. G., Bustinduy, A. L., Secor, W. E. & King, C. H. Human schistosomiasis. Lancet (London, England) \n                           383, 2253\u20132264, doi:10.1016\/s0140-6736(13)61949-2 (2014).","journal-title":"Lancet (London, England)"},{"key":"377_CR3","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1111\/imm.12105","volume":"139","author":"D Chen","year":"2013","unstructured":"Chen, D. et al. Characteristics of IL-17 induction by Schistosoma japonicum infection in C57BL\/6 mouse liver. Immunology \n                           139, 523\u2013532, doi:10.1111\/imm.12105 (2013).","journal-title":"Immunology"},{"key":"377_CR4","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1016\/j.pt.2012.09.005","volume":"28","author":"BJ Anthony","year":"2012","unstructured":"Anthony, B. J., Ramm, G. A. & McManus, D. P. Role of resident liver cells in the pathogenesis of schistosomiasis. Trends in parasitology \n                           28, 572\u2013579, doi:10.1016\/j.pt.2012.09.005 (2012).","journal-title":"Trends in parasitology"},{"key":"377_CR5","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1111\/j.1365-3024.2009.01098.x","volume":"31","author":"ML Burke","year":"2009","unstructured":"Burke, M. L. et al. Immunopathogenesis of human schistosomiasis. Parasite immunology \n                           31, 163\u2013176, doi:10.1111\/j.1365-3024.2009.01098.x (2009).","journal-title":"Parasite immunology"},{"key":"377_CR6","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/S1383-5769(03)00050-3","volume":"52","author":"M Hirata","year":"2003","unstructured":"Hirata, M. & Fukuma, T. Cytokine regulation in experimentally-induced Schistosoma japonicum egg granuloma formation. Parasitology international \n                           52, 341\u2013349 (2003).","journal-title":"Parasitology international"},{"key":"377_CR7","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1186\/1756-3305-3-60","volume":"3","author":"B Anthony","year":"2010","unstructured":"Anthony, B., Allen, J. T., Li, Y. S. & McManus, D. P. Hepatic stellate cells and parasite-induced liver fibrosis. Parasites & vectors \n                           3, 60, doi:10.1186\/1756-3305-3-60 (2010).","journal-title":"Parasites & vectors"},{"key":"377_CR8","doi-asserted-by":"publisher","first-page":"120","DOI":"10.1016\/j.tox.2008.06.013","volume":"254","author":"SL Friedman","year":"2008","unstructured":"Friedman, S. L. Hepatic fibrosis \u2013 overview. Toxicology \n                           254, 120\u2013129, doi:10.1016\/j.tox.2008.06.013 (2008).","journal-title":"Toxicology"},{"key":"377_CR9","doi-asserted-by":"publisher","first-page":"S15","DOI":"10.1016\/j.jhep.2015.02.039","volume":"62","author":"C Trautwein","year":"2015","unstructured":"Trautwein, C., Friedman, S. L., Schuppan, D. & Pinzani, M. Hepatic fibrosis: Concept to treatment. Journal of hepatology \n                           62, S15\u201324, doi:10.1016\/j.jhep.2015.02.039 (2015).","journal-title":"Journal of hepatology"},{"key":"377_CR10","doi-asserted-by":"publisher","first-page":"196","DOI":"10.3109\/08977194.2011.595714","volume":"29","author":"A Biernacka","year":"2011","unstructured":"Biernacka, A., Dobaczewski, M. & Frangogiannis, N. G. TGF-beta signaling in fibrosis. Growth factors (Chur, Switzerland) \n                           29, 196\u2013202, doi:10.3109\/08977194.2011.595714 (2011).","journal-title":"Growth factors (Chur, Switzerland)"},{"key":"377_CR11","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1016\/j.jhep.2015.04.011","volume":"63","author":"I Mannaerts","year":"2015","unstructured":"Mannaerts, I. et al. The Hippo pathway effector YAP controls mouse hepatic stellate cell activation. Journal of hepatology \n                           63, 679\u2013688, doi:10.1016\/j.jhep.2015.04.011 (2015).","journal-title":"Journal of hepatology"},{"key":"377_CR12","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1038\/nm1663","volume":"13","author":"E Seki","year":"2007","unstructured":"Seki, E. et al. TLR4 enhances TGF-beta signaling and hepatic fibrosis. Nature medicine \n                           13, 1324\u20131332, doi:10.1038\/nm1663 (2007).","journal-title":"Nature medicine"},{"key":"377_CR13","doi-asserted-by":"publisher","first-page":"2326","DOI":"10.1016\/j.biochi.2013.09.003","volume":"95","author":"CG Miao","year":"2013","unstructured":"Miao, C. G. et al. Wnt signaling in liver fibrosis: progress, challenges and potential directions. Biochimie \n                           95, 2326\u20132335, doi:10.1016\/j.biochi.2013.09.003 (2013).","journal-title":"Biochimie"},{"key":"377_CR14","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1586\/egh.10.74","volume":"4","author":"J Behari","year":"2010","unstructured":"Behari, J. The Wnt\/beta-catenin signaling pathway in liver biology and disease. Expert review of gastroenterology & hepatology \n                           4, 745\u2013756, doi:10.1586\/egh.10.74 (2010).","journal-title":"Expert review of gastroenterology & hepatology"},{"key":"377_CR15","doi-asserted-by":"publisher","first-page":"1294","DOI":"10.1053\/j.gastro.2015.02.056","volume":"148","author":"SP Monga","year":"2015","unstructured":"Monga, S. P. beta-Catenin Signaling and Roles in Liver Homeostasis, Injury, and Tumorigenesis. Gastroenterology \n                           148, 1294\u20131310, doi:10.1053\/j.gastro.2015.02.056 (2015).","journal-title":"Gastroenterology"},{"key":"377_CR16","doi-asserted-by":"publisher","first-page":"1298","DOI":"10.1002\/hep.21651","volume":"45","author":"MD Thompson","year":"2007","unstructured":"Thompson, M. D. & Monga, S. P. WNT\/beta-catenin signaling in liver health and disease. Hepatology (Baltimore, Md.) \n                           45, 1298\u20131305, doi:10.1002\/hep.21651 (2007).","journal-title":"Hepatology (Baltimore, Md.)"},{"key":"377_CR17","doi-asserted-by":"publisher","first-page":"G39","DOI":"10.1152\/ajpgi.00263.2007","volume":"294","author":"JH Cheng","year":"2008","unstructured":"Cheng, J. H. et al. Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. American journal of physiology. Gastrointestinal and liver physiology \n                           294, G39\u201349, doi:10.1152\/ajpgi.00263.2007 (2008).","journal-title":"American journal of physiology. Gastrointestinal and liver physiology"},{"key":"377_CR18","doi-asserted-by":"publisher","first-page":"2954","DOI":"10.1016\/j.febslet.2007.05.050","volume":"581","author":"SJ Myung","year":"2007","unstructured":"Myung, S. J. et al. Wnt signaling enhances the activation and survival of human hepatic stellate cells. FEBS letters \n                           581, 2954\u20132958, doi:10.1016\/j.febslet.2007.05.050 (2007).","journal-title":"FEBS letters"},{"key":"377_CR19","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1007\/s00204-013-1078-5","volume":"87","author":"P Godoy","year":"2013","unstructured":"Godoy, P. et al. Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME. Archives of toxicology \n                           87, 1315\u20131530, doi:10.1007\/s00204-013-1078-5 (2013).","journal-title":"Archives of toxicology"},{"key":"377_CR20","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1002\/hep.21473","volume":"45","author":"G Zeng","year":"2007","unstructured":"Zeng, G. et al. Wnt\u2019er in liver: expression of Wnt and frizzled genes in mouse. Hepatology (Baltimore, Md.) \n                           45, 195\u2013204, doi:10.1002\/hep.21473 (2007).","journal-title":"Hepatology (Baltimore, Md.)"},{"key":"377_CR21","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/j.exppara.2009.12.009","volume":"124","author":"B Anthony","year":"2010","unstructured":"Anthony, B., Mathieson, W., de Castro-Borges, W. & Allen, J. Schistosoma mansoni: egg-induced downregulation of hepatic stellate cell activation and fibrogenesis. Experimental parasitology \n                           124, 409\u2013420, doi:10.1016\/j.exppara.2009.12.009 (2010).","journal-title":"Experimental parasitology"},{"key":"377_CR22","doi-asserted-by":"publisher","first-page":"e68479","DOI":"10.1371\/journal.pone.0068479","volume":"8","author":"BJ Anthony","year":"2013","unstructured":"Anthony, B. J., James, K. R., Gobert, G. N., Ramm, G. A. & McManus, D. P. Schistosoma Eggs Induce a Proinflammatory, Anti-Fibrogenic Phenotype in Hepatic Stellate Cells. PloS one \n                           8, e68479, doi:10.1371\/journal.pone.0068479 (2013).","journal-title":"PloS one"},{"key":"377_CR23","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1016\/j.ijpara.2013.11.003","volume":"44","author":"Y Duan","year":"2014","unstructured":"Duan, Y. et al. \n                           Schistosoma japonicum soluble egg antigens induce apoptosis and inhibit activation of hepatic stellate cells: a possible molecular mechanism. International journal for parasitology \n                           44, 217\u2013224, doi:10.1016\/j.ijpara.2013.11.003 (2014).","journal-title":"International journal for parasitology"},{"key":"377_CR24","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1002\/hep.27332","volume":"61","author":"E Seki","year":"2015","unstructured":"Seki, E. & Schwabe, R. F. Hepatic inflammation and fibrosis: functional links and key pathways. Hepatology (Baltimore, Md.) \n                           61, 1066\u20131079, doi:10.1002\/hep.27332 (2015).","journal-title":"Hepatology (Baltimore, Md.)"},{"key":"377_CR25","doi-asserted-by":"publisher","unstructured":"Luedde, T., Kaplowitz, N. & Schwabe, R. F. Cell death and cell death responses in liver disease: mechanisms and clinical relevance. Gastroenterology \n                           147, 765\u2013783.e764, doi:10.1053\/j.gastro.2014.07.018 (2014).","DOI":"10.1053\/j.gastro.2014.07.018"},{"key":"377_CR26","doi-asserted-by":"publisher","first-page":"1696","DOI":"10.1111\/jgh.13065","volume":"30","author":"T Tu","year":"2015","unstructured":"Tu, T. et al. Hepatocytes in liver injury: Victim, bystander, or accomplice in progressive fibrosis? Journal of gastroenterology and hepatology \n                           30, 1696\u20131704, doi:10.1111\/jgh.13065 (2015).","journal-title":"Journal of gastroenterology and hepatology"},{"key":"377_CR27","doi-asserted-by":"publisher","first-page":"401","DOI":"10.1016\/j.jhep.2006.03.016","volume":"45","author":"F Jiang","year":"2006","unstructured":"Jiang, F., Parsons, C. J. & Stefanovic, B. Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. Journal of hepatology \n                           45, 401\u2013409, doi:10.1016\/j.jhep.2006.03.016 (2006).","journal-title":"Journal of hepatology"},{"key":"377_CR28","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1038\/nature12681","volume":"505","author":"BS Ding","year":"2014","unstructured":"Ding, B. S. et al. Divergent angiocrine signals from vascular niche balance liver regeneration and fibrosis. Nature \n                           505, 97\u2013102, doi:10.1038\/nature12681 (2014).","journal-title":"Nature"},{"key":"377_CR29","doi-asserted-by":"publisher","first-page":"739","DOI":"10.1002\/hep.26361","volume":"58","author":"D Xu","year":"2013","unstructured":"Xu, D. et al. Long noncoding RNAs associated with liver regeneration 1 accelerates hepatocyte proliferation during liver regeneration by activating Wnt\/beta-catenin signaling. Hepatology (Baltimore, Md.) \n                           58, 739\u2013751, doi:10.1002\/hep.26361 (2013).","journal-title":"Hepatology (Baltimore, Md.)"},{"key":"377_CR30","doi-asserted-by":"publisher","first-page":"572","DOI":"10.1038\/nm.2667","volume":"18","author":"L Boulter","year":"2012","unstructured":"Boulter, L. et al. Macrophage-derived Wnt opposes Notch signaling to specify hepatic progenitor cell fate in chronic liver disease. Nature medicine \n                           18, 572\u2013579, doi:10.1038\/nm.2667 (2012).","journal-title":"Nature medicine"},{"key":"377_CR31","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1038\/ng.722","volume":"43","author":"K Furuyama","year":"2011","unstructured":"Furuyama, K. et al. Continuous cell supply from a Sox9-expressing progenitor zone in adult liver, exocrine pancreas and intestine. Nature genetics \n                           43, 34\u201341, doi:10.1038\/ng.722 (2011).","journal-title":"Nature genetics"},{"key":"377_CR32","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1111\/j.1478-3231.2005.01192.x","volume":"26","author":"X Liu","year":"2006","unstructured":"Liu, X., Hu, H. & Yin, J. Q. Therapeutic strategies against TGF-beta signaling pathway in hepatic fibrosis. Liver international: official journal of the International Association for the Study of the Liver \n                           26, 8\u201322, doi:10.1111\/j.1478-3231.2005.01192.x (2006).","journal-title":"Liver international: official journal of the International Association for the Study of the Liver"},{"key":"377_CR33","doi-asserted-by":"publisher","unstructured":"Meindl-Beinker, N. M. & Dooley, S. Transforming growth factor-beta and hepatocyte transdifferentiation in liver fibrogenesis. Journal of gastroenterology and hepatology \n                           23 Suppl 1, S122\u2013127, doi:10.1111\/j.1440-1746.2007.05297.x (2008).","DOI":"10.1111\/j.1440-1746.2007.05297.x"},{"key":"377_CR34","doi-asserted-by":"publisher","first-page":"909","DOI":"10.1002\/hep.22397","volume":"48","author":"T Nitta","year":"2008","unstructured":"Nitta, T., Kim, J. S., Mohuczy, D. & Behrns, K. E. Murine cirrhosis induces hepatocyte epithelial mesenchymal transition and alterations in survival signaling pathways. Hepatology (Baltimore, Md.) \n                           48, 909\u2013919, doi:10.1002\/hep.22397 (2008).","journal-title":"Hepatology (Baltimore, Md.)"},{"key":"377_CR35","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1186\/1756-3305-7-148","volume":"7","author":"D Zhu","year":"2014","unstructured":"Zhu, D. et al. Expression of microRNA-454 in TGF-beta1-stimulated hepatic stellate cells and in mouse livers infected with Schistosoma japonicum. Parasites & vectors \n                           7, 148, doi:10.1186\/1756-3305-7-148 (2014).","journal-title":"Parasites & vectors"},{"key":"377_CR36","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1007\/s00441-011-1246-y","volume":"347","author":"S Dooley","year":"2012","unstructured":"Dooley, S. & ten Dijke, P. TGF-beta in progression of liver disease. 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Liver international: official journal of the International Association for the Study of the Liver \n                           28, 1065\u20131079, doi:10.1111\/j.1478-3231.2008.01826.x (2008).","journal-title":"Liver international: official journal of the International Association for the Study of the Liver"},{"key":"377_CR46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/S1386-6346(03)00115-3","volume":"26","author":"AW Rachfal","year":"2003","unstructured":"Rachfal, A. W. & Brigstock, D. R. Connective tissue growth factor (CTGF\/CCN2) in hepatic fibrosis. Hepatology research: the official journal of the Japan Society of Hepatology \n                           26, 1\u20139 (2003).","journal-title":"Hepatology research: the official journal of the Japan Society of Hepatology"},{"key":"377_CR47","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1002\/hep.23102","volume":"50","author":"Z Tong","year":"2009","unstructured":"Tong, Z. et al. 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